1. Field of the Invention
The invention relates to pharmaceutical use of diterpene compounds; particularly, to pharmaceutical use of a coral-produced diterpene, excavatolide B, from a coral or an analogue thereof.
2. Description of the Related Art
With the progression of civilization, we human beings not only have longevity, but also emphasize the quality of our daily lives. However, a specific and effective drug is still absent for many diseases nowadays, such as cancer, chronic pain and atherosclerosis.
Inflammation has been proven to play an important role in the occurrence of several diseases in many studies. The occurrence of the inflammation-related diseases is highly associated with chronic and long-term inflammation induced by free radicals, pollution, food, ages, and pressure.
Atherosclerosis leads to remold a blood vessel and further causes the reduction of the inside diameter of the vessel. Therefore, it is an important risk factor of one of the leading causes of death, acute and lethal cardiovascular diseases, such as myocardial infarction, stroke and peripheral vascular diseases (Libby, Am J Clin Nutr 83:456 S-460S, 2006). Atherosclerosis is proven to be a chronic inflammatory cardiovascular disease (Ross, N Engl J Med 340: 115-126, 1999). When intima cells of the blood vessel are pressed or injured, monocytes are induced to differentiate into macrophages and accumulate abundantly around the injured tissue. Through a series of inflammatory reactions, smooth muscle cells of the blood vessel proliferate and inflammatory cells accumulate, and such reactions damage the blood flow and lead to cardiovascular diseases finally (Lucas and Greaves, Exp Rev Mol Med 3:1-18, 2001; Gordon, Bioassays 17:977-986, 1995; Majno and Joris, Cells, Tissues and Disease: Principles of General Pathology, Blackwell Science, Cambridge, Mass., USA, 1996). In animal model studies, the inflammatory critical factors of inducible nitric oxide synthase and cyclooxygenase-2 are shown to play an important role in atherosclerosis (Cipollone, Lupus 14:756-759, 2005; Boyle, Curr Vasc Pharmacol 3:63-68, 2005). Furthermore, bulk of inducible nitric oxide synthase and cyclooxygenase-2 is expressed in the human atherosclerosis tissue that comprises macrophages and proliferated smooth muscle cells (Baker et al, Arterioscler Thromb Vasc Biol 19:646-655, 1999; Buttery et al, Lab Invest 75:77-85, 1996). Presently, inducible nitric oxide synthase and cyclooxygenase-2 inhibitors are proven to significantly prevent the occurrence of atherosclerosis (Burleigh et al, Circulation 105:1816-23, 2002; Hayashi et al, Atherosclerosis 187:316-324, 2006; Pratico et al, Arterioscler Thromb Vasc Biol 19:646-655, 2001).
According to the definition made by International Association for the Study of Pain (IASP), pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. With the extension of longevity, the opportunities and duration of pain are raised. To estimate in the conservative way, the global anodyne consumption reaches around one hundred billion US dollars. Improving life quality through pain control is an important subject. Among various pains, the factors of neuropathic pain are diverse, such as reduced distal circulation due to diabetes mellitus, neuron damage due to amputation or injury, viral infection and unknown reasons. Clinically, anodynes are divided into addictive anodynes and non-addictive anodynes. The addictive anodyne mainly comprises opiate, but the effect thereof to neuropathic pain is not satisfactory. The non-addictive anodyne comprises a steroid type and a non-steroid type. The steroid anodyne relives pain mainly through an anti-inflammatory pathway. However, the steroid anodyne is nonspecific, and the side effects are significant. The long-term usage is prohibited. On the other hand, the non-steroid anodyne comprises a pain-relieving type (such as panadol) and an anti-inflammatory type (such as aspirin). A non-steroid anti-inflammatory drug (NSAID) is now known to be safe with fewer side effects. The mechanism of a specific NSAID is through inhibiting inducible nitric oxide synthase and cyclooxygenase-2 pathways to relieve pain (Turini and DuBois, Annual Rev Med 53:35, 2002; Handy et al, Br J Pharmacol 123:1119-1126, 1998; Osborne et al, Br J Pharmacol 126:1840-1846, 1999). The product of NO or PGE2 catalyzed by inducible nitric oxide synthase or cyclooxygenase-2 is shown to be critical to the occurrence, maintenance and sensitivity of pain in the central neural system and periphery tissues (Moalem and Tracey, Brain Res Rev 51:240-264, 2006). Compared to using nerve blockers for pain relieving, administering inducible nitric oxide synthase and cyclooxygenase-2 inhibitors does not affect movement and neuron. Therefore, it is an important aspect for drug development.
Skin is the largest organ in the body. As the primary interface between the body and environment, it serves as the first line of defense against microbial pathogens as well as physical and chemical stress or insults (Kupper T S, Fuhlbrigge R C. Nature reviews Immunology 2004, 4:211-222; Nestle F O, Di Meglio P, Qin J Z, Nickoloff B J. Nature reviews Immunology 2009, 9:679-691). The skin does not only serve as a physical and a chemical barrier, but is also an immune-competent organ that elicits effective innate and adaptive immune responses to protect the human body. The cutaneous immune system maintains a balance between restricting excessive inflammation following tissue damage or injury and preserving the ability to rapidly respond to pathogen infection (Jermy A. Nature Reviews Immunology 2010, 10:1). It is clear that inadequate or misdirected immune response is involved in the pathogenesis of a variety of acquired inflammatory skin disorders (Kupper T S, Fuhlbrigge R C. Nature reviews Immunology 2004, 4:211-222). Therefore, systematic investigation of the mechanisms of action of immunomodulatory agents on the skin's immune system is necessary for the development of therapies for skin disorders.
Acute inflammation is the initial immune response to harmful stimuli. Acute inflammation in the skin often involves an increase in the vascular permeability of skin tissues, resulting in an accumulation of fluid at the inflamed site (edema). The release of mediator molecules such as nitric oxide and prostaglandins also elicits vascular permeability, thus permitting the efficient migration of leukocytes, mainly neutrophils, to the inflamed tissue site. Matrix metalloproteinase-9 (MMP-9) has been reported to be a crucial player in such neutrophil migration by degrading some major cellular components of the epidermis and dermis (Nagaoka I, Hirota S. Inflamm Res 2000, 49:55-62). In addition, it is well-known that secretions of cytokines such as TNF-α, IL-1α and IL-6 by keratinocytes or antigen-specific cells can play a key role in mediating the cutaneous inflammatory response (Nestle F O, Di Meglio P, Qin J Z, Nickoloff B J. Nature reviews Immunology 2009, 9:679-691; De Vry C G, Valdez M, Lazarov M, Muhr E, Buelow R, Fong T, Iyer S. J Invest Dermatol 2005, 125:473-481; Cumberbatch M, Dearman R J, Kimber I Immunology 1996, 87:513-518). These mediators were employed as indicators of skin inflammation in this study.
Several novel approaches have been explored to manage risk factors for skin cancers, tissue damage from UVB exposure, and inflammatory skin disorders (Stanifortha V, Huang W C, Aravindaram K, Yang N S. The Journal of Nutritional Biochemistry, In Press). Several phytochemicals and tissue extracts from medicinal plants have been reported to confer immunostimulatory activities and have potential clinical applications (Nair H B, Sung B, Yadav V R, Kannappan R, Chaturvedi M M, Aggarwal B B. Biochem Pharmacol 2010, 80:1833-1843; Wang C Y, Staniforth V, Chiao M T, Hou C C, Wu H M, Yeh K C, Chen C H, Hwang P I, Wen T N, Shyur L F, Yang N S. BMC Genomics 2008, 9:479). A small phytochemical from Lithospermum erythrorhizon (shikonin) is previously reported to be able to inhibit the transcriptional activation of human TNF-α promoter in vivo in mouse skin (Staniforth V, Wang S Y, Shyur L F, Yang N S. J Biol Chem 2004, 279:5877-5885).
Caffeic acid is also shown to suppress UVB radiation-induced expression of IL-10 and activation of MAPKs in mouse skin tissues (Staniforth V, Chiu L T, Yang N S. Carcinogenesis 2006, 27:1803-1811). More recently, ferulic acid, a phenolic phytochemical, is demonstrated to be able to effectively inhibit UVB-induced matrix metalloproteinases in mouse skin via a posttranslational mechanism (Stanifortha V, Huang W C, Aravindaram K, Yang N S. The Journal of Nutritional Biochemistry, 2012, 23:443-451).
Natural products from plants and terrestrial microorganisms have traditionally provided good sources of lead compounds/agents for human medicines. However, due to the biological diversity of the marine environment and the discovery of marine compounds with certain unique structures and pharmacological activities, compounds from marine organisms are expected to be a major source of lead compounds for future generations of pharmaceuticals (Marris E. Nature 2006, 443:904-905). A spectrum of different novel marine compounds have been identified, and their bioactivities evaluated for potential pharmaceutical application (Blunt J W, Copp B R, Munro M H, Northcote P T, Prinsep M R. Nat Prod Rep 2005, 22:15-61). Marine organisms are a possible extracting source of pharmaceutical compounds.